A targeting construct containing the neomycin and HSTK genes and 10 kb of DNA genomic homology was constructed to disrupt the Muc5ac gene by homologous recombination. The construct was electroporated into mouse ES cells and 2 PCR positive clones of 170 clones analyzed were obtained. PCR and genomic Southern analysis verified targeting. Chimeras have been generated and 21 germline agouties have been obtained. The heterozygous Muc5ac mice are now being breed to generate wild type and Muc5ac-/- mice generated for lung inflammation and gastric ulceration studies.